WO2008089936A1 - Nouveaux marqueurs pour la néphropathie chronique - Google Patents

Nouveaux marqueurs pour la néphropathie chronique Download PDF

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WO2008089936A1
WO2008089936A1 PCT/EP2008/000420 EP2008000420W WO2008089936A1 WO 2008089936 A1 WO2008089936 A1 WO 2008089936A1 EP 2008000420 W EP2008000420 W EP 2008000420W WO 2008089936 A1 WO2008089936 A1 WO 2008089936A1
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kidney disease
adiponectin
progression
fgf23
chronic kidney
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PCT/EP2008/000420
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English (en)
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Florian Kronenberg
Barbara Kollerits
Danilo Fliser
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Medizinische Universität Innsbruck
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Priority to EP08707153A priority Critical patent/EP2115168A1/fr
Priority to US12/523,625 priority patent/US8058015B2/en
Publication of WO2008089936A1 publication Critical patent/WO2008089936A1/fr
Priority to US13/280,719 priority patent/US8623607B2/en

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    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
    • C12Q1/6876—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes
    • C12Q1/6883—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q2600/00—Oligonucleotides characterized by their use
    • C12Q2600/112—Disease subtyping, staging or classification
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q2600/00—Oligonucleotides characterized by their use
    • C12Q2600/118—Prognosis of disease development

Definitions

  • the present invention relates to a method for the determination or prediction of the progression of chronic kidney disease in a subject suspected to suffer from chronic kidney disease, said method comprising the step of determining the expression levels of at least one marker selected from (a) FGF23; and (b) adiponectin in a biological sample. Furthermore, the present invention relates to a use of a specific detection molecule for FGF23 or use of a specific detection molecule for adiponectin for the preparation of a diagnostic composition for the detection of chronic kidney disease or the progression of chronic kidney diseases in a subject suspected to suffer from said disease.
  • the present invention also provides for use of FGF23 and/or of adiponectin as an in vitro marker for the progression of a chronic kidney disease and kits comprising a specific detection molecule for FGF23 or a specific detection molecule for adiponectin for use in the method of the present invention.
  • kidney contains a vast amount of vessels of different size and function with an enormous endothelial surface.
  • pathophysiological conditions involving the vascular bed are not only related to atherosclerotic changes of major vessels of the heart and the brain, but also to vascular changes within the kidney.
  • glomerulosclerosis and atherosclerosis share common pathophysiological pathways (Kasiske, (1987) Kidney Int. 31 , 1153-1159).
  • factors related to atherosclerosis as well as glomerular-endothelial injury might be interesting candidates to be involved in the progression of kidney disease.
  • adiponectin the major adipocyte secretory protein. It has been demonstrated to improve insulin sensitivity and to possess antiinflammatory and anti-atherosclerotic properties (Rabin, (2005) Expert Rev. Cardiovasc. Ther. 3, 465-471). Hypoadiponectinaemia has been found to be associated with insulin resistance (Weyer, (2001) J. Clin. Endocrinol. Metab. 86, 1930-1935; Zoccali, (2002) J. Am. Soc. Nephrol.
  • Disturbed calcium-phosphate metabolism affects cardiovascular morbidity and mortality in patients with chronic kidney disease (CKD), and particularly in patients with end-stage renal disease (Block, (2004) J. Am. Soc. Nephrol. 15, 2208-2218; Schmitt, (2006) J. Am. Soc. Nephrol. 17 (Suppl. 2), S78-80). So far, it has not been firmly established whether it also contributes to CKD progression.
  • potential culprits for progression are hyperphosphatemia, hyperparathyroidism, lack of active vitamin D, and possibly excess of the phosphaturic hormone fibroblast growth factor 23 (FGF23) (Ritz, (2005) Kidney Int. 68 (Suppl.
  • the present invention relates to a method for the determination or prediction of the progression of chronic kidney disease in a subject suspected to suffer from chronic kidney disease, said method comprising the step of determining the expression levels of at least one marker selected from a) FGF23; and b) adiponectin in a biological sample.
  • the fibroblast growth factor 23 (FGF-23) and adiponectin are, independently (but also in combination), very predictive markers for the progression of chronic kidney disease (CKD). Accordingly, the two markers identified herein are very useful indicators of the progression of the disease, in particular in non-diabetic patients. Especially FGF23 is a particularly good and also independent predictor for progression of CKD, in particular in non-diabetic patients. It is of note that in particular in male human patients both markers (FGF23 and adiponectin) may be measured in order to determine the progression or potential progression of CKD.
  • the values for the expression level or the corresponding quantitative values of FGF-23 and/or adiponectin are useful in the prediction of a progression, in particular also and specifically for fast progression of CKD.
  • a "fast progression” is meant that the progression endpoint is reached significantly faster, e.g. at least 10% or at least 20% or at least 30% faster when compared to an average (clinical or disease) progression.
  • two a "fast progression" to the (renal) progression endpoint was reached in about 40 to 50 month (average 46.9 month), whereas in slower progression said endpoint was reached in about 65 to 80 month (average 72.5 month).
  • the present invention now provides for a needed diagnostic tool for practitioners (like, clinicians) in order to determine whether a progression of CKD is fast or slow or whether said CKD has the potential of a fast or slow progression. This is of particular importance since the clinical avenues to be taken in order to ameliorate the medical condition of a CKD patient (human as well as non-human patients) depends on the prediction how the disease will develop/progress; see also experimental part of this invention and further description herein below
  • the gist of the present invention can, inter alia, be seen in the provision of method for the determination of the (potential) progression of CKD. Also the corresponding means and methods are provided herein.
  • the present invention provides for the teaching that a clear and strong correlation between the expression level of fibroblast growth factor 23/FGF23 (and/or of adiponectin) and the progression of chronic kidney disease (CKD) can be drawn.
  • the determination of "expression levels” is, e.g., carried out by a comparison of the expression levels to be determined (in a given test sample) with (for example) corresponding standard controls or base line values. Standard controls/baseline values and the like are explained in detail herein below.
  • the present invention also provides for an in vitro method for the determination of the progression of CKD, said method comprising the step of determining the expression level of FGF23 and/or of adiponectin in a sample from a subject to be analyzed (test sample) and comparing said expression level of FGF23 and/or of adiponectin to baseline values (or normal standards or optimal cut-off rates or the like; control sample) and determining whether said test sample comprises a higher expression level of FGF23 and/or of adiponectin than the corresponding sample, whereby the elevated FGF23 and/or of adiponectin is indicative and correlated to the progression of the chronic kidney disease.
  • Another important finding of the present invention is that the correlation of FGF23 expression level(s) and the progression of CKD appears to be independent form sex/gender, whereas adiponectin is a particular good marker for the progression of CKD in male subject, in particular human male subjects. It is also important to note that the correlation of FGF23 and adiponectin expression level(s) with the progression of CKD is independent from GFR.
  • the cut-off for this assay can be extrapolated by adjusting for the systematic differences between the two assays. If the assay used herein shows a mean value of e.g. 150 rU/ml and the other assay shows a mean value of 200 ⁇ g/mL, the optimal cutoff for the latter assay has to be increased by 30% compared to assay used herein and illustrated in the appended examples.
  • the described method for the determination or prediction of the progression of chronic kidney disease preferably is performed on a human subject, it is evident for the skilled artisan that the method of the present invention may also be useful for the determination or prediction of the progression of chronic kidney disease of other animal species than humans.
  • the method of the present invention is also useful for determining or predicting the progression of chronic kidney disease of domesticated animals including, but not limited to, dogs (Canis lupus familiaris) cats (Felis silvestris catus) and horses (Equus caballus). Particularly preferred are male dogs, cats and horses, e.g. stallions.
  • a blood (serum or plasma) level of more than 100rU/ml (specifically 104rU/ml) of FGF23 and an adiponectin level above the optimal cut-off of more than 3 ⁇ g/ml (e.g.. 4/yg/ml) is indicative for a faster progression of CKD.
  • the values provide herein are non-limiting values for human subjects Again, it is of note values provided herein are illustrative and the skilled artisan is aware of the fact that such values are assay/test dependant.
  • ROC Receiver Operating Characteristics
  • the Receiver Operating Characteristics (ROC) curve derives its name from its first application - measuring the ability of radar operators to distinguish radar signals from noise.
  • a graph is constructed with sensitivity (sometimes labeled as the true-positive rate) on the vertical axis, and 1-specificty (sometimes labeled as the false-positive rate) on the horizontal axis.
  • sensitivity and 1 -specif icity will be calculated.
  • ROC Receiver Operating Characteristics
  • progression of chronic kidney disease or “chronic kidney disease progression” means , for example, a doubling of baseline serum (or plasma) creatinine concentration and/or terminal real failure necessitating renal replacement therapy, like dialysis (hemodialysis, peritoneal dialysis) or even renal transplantation.
  • the definition of the "progression of chronic kidney disease” is very well known in the art and is, inter alia illustrated in Brenner and Rector “The Kidney”, (2004) Saunders pub. Philadelphia. Accordingly, the “progression of chronic kidney disease” can be determined, in a primary endpoint, as the doubling of the base-line serum creatinine or the need for dialysis or kidney transplantation; see also Maschio (1996) N. Engl. J. Med 334, 939-945.
  • Determining the expression levels of any one of the two markers defined herein means of the treatment that the protein concentration, in particular in blood serum and/or blood plasma is to be determined, i.e. as a function of protein expression and/or presence of the protein in the corresponding biological samples, like blood, serum or plasma.
  • the claimed method comprises the determination of the expression level of said adiponectin in biological samples from male subjects (in particular human male subjects/patients) suspected to suffer from chronic kidney disease
  • the herein defined marker adiponectin is a surprisingly strong predictive marker for the progression of CKD in male patients, in particular human male patients.
  • the subject suspected to suffer from chronic kidney disease may show renal impairment or dysfunction (e.g. elevated creatinine levels, decrease of GFR, and the like),or from primary kidney disease.
  • the present invention and the methods provided herein are also envisaged to be useful in other forms of chronic kidney disease, like diabetic nephropathy.
  • the focus of this invention is in the experimental part laid on non-diabetic kidney impairments.
  • kidney disease is a non-diabetic kidney disease, however also in diabetic patients the progression of CKD may be measured, analyzed and/or evaluated by the use of the means and methods provided herein.
  • the methods provided herein are in particular useful in the determination (i.e. measurement, analysis and/or evaluation) of the progression of a chronic kidney disease, like a primary kidney disease whereby said primary kidney disease may be selected from the group consisting of glomerulonephritis, adult polycystic kidney disease, and interstitial nephritis and various other types of kidney disease including even patients in whom the exact diagnosis is unknown.
  • a known diabetic kidney disease the progression of which may be assessed by the methods provided here may be diabetic nephropathy.
  • said expression level of said at least one marker selected from FGF23 and/or adiponectin is determined in a biological sample from a subject suspected to suffer from chronic kidney disease and said expression level is compared to a standard control or a reference sample.
  • a standard control may be or can be derived from a biological sample of a healthy control individual or from healthy control individuals of the same species as the subject suspected to suffer from a chronic kidney disease. It is also possible that such a standard control is or is derived from an earlier sample from the patient to be diagnosed, i.e. an older blood-, serum- or plasma- sample which was obtained before the onset of CKD.
  • said determination of the expression levels of at least one marker selected from FGF23 and/or adiponectin comprises the detection of the FGF23 protein and/or the adiponectin protein in said biological sample or said biological samples. This is also illustrated in the appended examples.
  • FGF23 in context of this invention is the fibroblast growth factor 23.
  • the FGF23 gene encodes a member of the fibroblast growth factor family that is mutant in autosomal dominant hydrophosphatemic rickets (ADHR; 193100).
  • the FGF23 coding nucleic acid sequence as well as the corresponding amino acid sequence of human FGF23 (SEQ ID NO: 1 for the nucleic acid sequence and SEQ ID NO: 2 for the amino acid sequence), cat FGF23 (SEQ ID NO: 3 for the nucleic acid sequence and SEQ ID NO: 4 for the amino acid sequence) and dog FGF23 (SEQ ID NO: 5 for the nucleic acid sequence and SEQ ID NO: 6 for the amino acid sequence) is provided.
  • Human FGF23 sequences can also be obtained under NM_020638 or NP_065689 in NCBI Build 35.1 Ensembl.
  • a corresponding reference sequence of human FGF23 is also provided in the appended Figure 5 (nucleic acid molecule and amino acid sequence).
  • nucleic acid sequence and/or the corresponding amino acid sequence of FGF23 of other animal species than the herein provided sequences for human-, cat- and dog FGF23 can be identified by the skilled person using methods known in the art, e.g. by using hybridization assays or by using alignments, either manually or by using computer programs such as those mentioned herein below in connection with the definition of the term "hybridization” and degrees of homology.
  • the nucleic acid sequence encoding for orthologs of human FGF23 is at least 70%, at least 75%, at least 78%, at least 80%, more preferably at least 90% homologous to the nucleic acid sequence as shown in SEQ ID NO. 1 or the amino acid sequence as shown in SEQ ID NO. 2 or the nucleic acid or amino acid sequences shown in Figure 5.
  • adiponectin is very well known in the art and is an adipokine with potent antiinflammatory and anti-atherosclerotic properties.
  • adiponectin is very well known in the art and is an adipokine with potent antiinflammatory and anti-atherosclerotic properties.
  • cat adiponectin SEQ ID NO: 9 for the nucleic acid sequence and SEQ ID NO: 10 for the amino acid sequence
  • dog adiponectin SEQ ID NO: 11 for the nucleic acid sequence and SEQ ID NO: 12 for the amino acid sequence
  • Human adiponectin sequences can also be obtained NM_004797, NP_004788.1 on the NCBI database (build 35.1 Ensembl).
  • a corresponding reference sequence of human adiponectin is also provided in the appended Figure 6 (nucleic acid molecule and amino acid sequence).
  • nucleic acid sequence and/or the corresponding amino acid sequence of adiponectin of other animal species than the herein provided sequences for human-, cat- and dog adiponectin can be identified by the skilled person using methods known in the art, e.g. by using hybridization assays or by using alignments, either manually or by using computer programs such as those mentioned herein below in connection with the definition of the term "hybridization" and degrees of homology.
  • the nucleic acid sequence encoding for orthologs of human adiponectin is at least 75%, at least 80%, at least 83%, at least 85%, more preferably at least 90% homologous to the nucleic acid sequence as shown in SEQ ID NO. 7 or the amino acid sequence as shown in SEQ ID NO: 8.or the nucleic acid or amino acid sequences as shown in Figure 6.
  • Hybridization assays for the characterization of orthologs of known genes/proteins are well known in the art; see e.g. Sambrook, Russell “Molecular Cloning, A Laboratory Manual”, Cold Spring Harbor Laboratory, N. Y. (2001 ); Ausubel, “Current Protocols in Molecular Biology", Green Publishing Associates and Wiley Interscience, N. Y. (1989).
  • the term “hybridization” or “hybridizes” as used herein may relate to hybridizations under stringent or non-stringent conditions. If not further specified, the conditions are preferably non-stringent. Said hybridization conditions may be established according to conventional protocols described, e.g., in Sambrook (2001 ) loc. cit.; Ausubel (1989) loc.
  • the terms "homology” or “percent homology” or “identical” or “percent identity” in the context of two or more nucleic acid or amino acid sequences refers to two or more sequences or subsequences that are the same, or that have a specified percentage of amino acid residues or nucleotides that are the same (e.g. 75% identity, preferably, 80% identity, more preferably 83-85% identity, most preferably at least 90% identity), when compared and aligned for maximum correspondence over a window of comparison, or over a designated region as measured using a sequence comparison algorithm as known in the art, or by manual alignment and visual inspection. Sequences having, for example, 75% to 90% or greater sequence identity may be considered to be substantially identical.
  • Such a definition also applies to the complement of a test sequence.
  • the described identity exists over a region that is at least about 15 to 25 amino acids or nucleotides in length, more preferably, over a region that is about 50 to 100 amino acids or nucleotides in length.
  • Those having skill in the art will know how to determine percent identity between/among sequences using, for example, algorithms such as those based on CLUSTALW computer program (Thompson Nucl. Acids Res. 2 (1994), 4673-4680) or FASTDB (Brutlag Comp. App. Biosci. 6 (1990), 237-245), as known in the art.
  • the BLASTP program uses as defaults a wordlength (W) of 3, and an expectation (E) of 10.
  • BLAST 2.0 which stands for Basic Local Alignment Search Tool BLAST (Altschul (1997), loc. cit.; Altschul (1993), loc. cit.; Altschul (1990), loc. cit.), can be used to search for local sequence alignments.
  • BLAST as discussed above, produces alignments of both nucleotide and amino acid sequences to determine sequence similarity. Because of the local nature of the alignments, BLAST is especially useful in determining exact matches or in identifying similar sequences.
  • the fundamental unit of BLAST algorithm output is the High-scoring Segment Pair (HSP).
  • HSP High-scoring Segment Pair
  • An HSP consists of two sequence fragments of arbitrary but equal lengths whose alignment is locally maximal and for which the alignment score meets or exceeds a threshold or cut-off score set by the user.
  • the BLAST approach is to look for HSPs between a query sequence and a database sequence, to evaluate the statistical significance of any matches found, and to report only those matches which satisfy the user-selected threshold of significance.
  • the parameter E establishes the statistically significant threshold for reporting database sequence matches.
  • E is interpreted as the upper bound of the expected frequency of chance occurrence of an HSP (or set of HSPs) within the context of the entire database search. Any database sequence whose match satisfies E is reported in the program output.
  • test systems/assay systems used to determine the expression level of FGF23 and/or adiponectin are adapted to the animal species to be tested.
  • a test system/assay system suitable for measuring human FGF23 or human adiponectin is used to measure FGF23 and/or adiponectin in human subjects.
  • the biological sample to be used and/or assayed in the method of the present invention may be a tissue sample, a cell sample or a sample derived from a biological fluid, like blood, feces, urine. Particular preferred is whole blood, blood serum or blood plasma.
  • the determination of the expression levels of at least one marker selected from FGF23 and adiponectin in the method of the present invention comprises, inter alia, a quantitative measurement of said marker or said markers.
  • Quantitative measurement may comprise an immunological assay or an immunodetection assay.
  • commercial ELISA kits for FGF-23 are currently available from lmmutopics US (Cat Number:60-6500; the exemplified ELISA used in the appended examples) Kainos Laboratories (Cat. Number CY-4000) , ALPCA Catalog Number 31 -60-6500 or Osteomedical Group (Cat. Number 60-6500).
  • Kainos Laboratories Cat. Number CY-4000
  • ALPCA Catalog Number 31 -60-6500 or Osteomedical Group
  • the corresponding test systems and assays need corresponding adjustments and evaluation in order to standardize the test for the measurement of "elevated FGF-23 levels".
  • definitive values are dependent on the test/assay system used.
  • Such assays are known in the art and may comprise EIA (Enzyme lmmuno Assay), FIA (Fluorescent lmmuno Assay), and CLIA (Chemiluminescent Immune Assay) or Western Blots.
  • EIA Enzyme lmmuno Assay
  • FIA Fluorescent lmmuno Assay
  • CLIA Cellular Immune Assay
  • an elevated expression level of FGF23 and/or adiponectin as compared to a standard control or a reference sample is in particular indicative for the progression of said chronic kidney disease.
  • the inventive method described herein is in particular of relevance when an elevated level of at least 10OrU/ml (with the specific assay system from lmmutopics US (Cat Number:60-6500) employed in the appended examples this value is 104rU/ml) are measured since said elevated level of FGF23 protein is predictive for a fast progression of said chronic kidney disease.
  • the specific numerical value is dependant on the test system used and needs to be compared to the data provided herein and/or needs to be validated with healthy controls/healthy control samples. Accordingly, also higher or lower numerical values for the FGF-23 concentration (e.g. in plasma or serum) can be predictive for the faster progression of CKD, as long as this level is elevated in comparison to (a) (healthy) control(s)/control sample(s).
  • an elevated level of at least 3 /vg/ml (with the specific test/assay system used in the experimental part, namely the "Human Adiponectin (Acrp 30) Quantikine ELISA Kit form R&D Systems a value of 4/yg/ml) of adiponectin protein in human male subjects is predictive for a fast progression of said chronic kidney disease.
  • the specific numerical value is dependant on the test system used and needs to be compared to the data provided herein and/or needs to be validated with healthy controls/healthy control samples. Accordingly, also higher or lower numerical values for the adiponectin concentration (e.g.
  • the inventive method may further comprise the measurement of further, additional markers or of further, additional physiological parameters, like a determination of the glomerular filtration rate.
  • Said glomerular filtration rate may be determined by use of the iohexol or iothalamate clearance technique, as also illustrated in the appended examples or by calculation such as by the Cockcroft and Gault formula (Cockcroft (1976) Nephron 16, 31-41), or the MDRD formula (Lhotta (2005) Deutsche Medizinische Klischrift 130:2021-24). Such methods are well known in the art, see, inter alia Brenner and Rector "The Kidney” (2004), loc. cit.
  • the glomerular filtration rate is considered predictive for the progression of said chronic kidney disease. This means the worse the kidney function estimated by the glomerular filtration rate is at the time of examination (meaning the lower the GFR is), the higher is the probability of a progression of said chronic kidney disease. As illustrated tables provided herein, a patient having a GFR that is 10 ml/min/1.73 m 2 higher in comparison to another test person has a probability to show a progression probability of 0.80, i.e. a 20% lower probability to experience a progression of the disease during the investigated observation period.
  • An elevated ApoA-IV concentration of at least 3 mg/dl is predictive for the progression of said chronic kidney disease.
  • Fibroblast growth factor 23 (rU/mL) with progression of kidney disease during the observation period using a multiple Cox Proportional Hazards regression model is provide in the following, illustrative table:
  • FGF23 (10 rU/mL) 1.015 (1.007-1.023) ⁇ 0.001
  • Adiponectin (1 ⁇ g/mL) 1.16(1.08-1.23) ⁇ 0.001
  • FGF23 (10 rU/ml_) 1.014 (1.004-1.025) 0.01
  • adiponectin levels of 1 //g/mL increases the risk of progression by 14% (HR of 1.14).
  • the very small p-value of ⁇ 0.001 also indicates the high predicitve value of adiponectin.
  • a p-value should generally be lower than p ⁇ 0.05 in order to be considered as statistically significant
  • Also provided herein is the use of a specific detection molecule for FGF23 or use of a specific detection molecule for adiponectin for the preparation of a diagnostic composition for the detection of chronic kidney disease or the progression of chronic kidney diseases in a subject suspected to suffer from said disease.
  • Said detection molecule may be selected from the group consisting of an antibody, an antibody fragment, an antibody derivative, an aptamer.
  • the said detection molecule is an antibody for FGF-23.
  • antibodies are known in the art and, inter alia comprised in the assay commercially available from: lmmutopics Inc., San Clemente, USA; (Cat, Number 60-6500).
  • Adiponectin was measured with an ELISA (R&D Systems, Minneapolis, MN)).
  • an antibody for the detection of adiponectin as provided by R&D Systems as "Human adiponectin (Acrp30) Quantikine ELISA kit.
  • binding molecules like antibodies, which can easily be used in test assays/test systems for the detection and in particular quantification of the protein level of FGF 23 and/or adiponectin, in particular in (human) serum and plasma probes.
  • kits are provided wherein FGF-23 and/or adiponectin are to be measured (for example with immunological/immunobiochemical tests, like ELISA) in order to deduce whether a given patient is likely to suffer from a faster progression of chronic kidney disease.
  • kits comprising a specific detection molecule for FGF23 or a specific detection molecule for adiponectin for use in the inventive method for the detection of (fast or faster) progression of kidney disease.
  • the kit of the present invention further comprises, optionally (a) reaction buffer(s), storage solutions and/or remaining reagents or materials required for the conduct of scientific or diagnostic assays or the like.
  • parts of the kit of the invention can be packaged individually in vials or bottles or in combination in containers or multicontainer units.
  • kit of the present invention may be advantageously used as diagnostic kits, as research tools or therapeutic tools. Additionally, the kit of the invention may contain means for detection suitable for medical and/or diagnostic purposes.
  • manufacture of the kits follows preferably standard procedures which are known to the person skilled in the art. The figures show:
  • FIG. 1 Receiver operating characteristics (ROC) curve of glomerular filtration rate (GFR) and plasma fibroblast growth factor 23 (FGF23) concentrations with progression of kidney disease as status variable.
  • ROC Receiver operating characteristics
  • AUC area under the curve
  • Figure 2 Kaplan-Meier curves of renal endpoints in patients with below and above optimal cut-off of plasma fibroblast growth factor 23 (FGF23) concentrations.
  • FGF23 plasma fibroblast growth factor 23
  • FIG. 2 Kaplan-Meier curves of renal endpoints in patients with below and above optimal cut-off of plasma fibroblast growth factor 23 (FGF23) concentrations.
  • FGF23 levels above the optimal cut-off i.e. above 104 rU/mL
  • progression was significantly faster (log-rank test, p ⁇ 0.0001).
  • Numbers near the survival curves represent the number of patients at risk with FGF23 levels below and above the optimal cut-off at the times 0, 12, 24, 36, 48, 60 and 72 months.
  • Figure 3 Kaplan-Meier curves of renal endpoints in male (upper panel) and female (lower panel) patients with plasma adiponectin concentrations above and below the sex-specific cut-off of 4 /yg/mL.
  • Numbers near the survival curves represent the number of patients at risk with plasma adiponectin levels below and above the cut-off at the times 0, 12, 24, 36, 48, 60 and 72 months.
  • Figure 5 Exemplary coding sequence and corresponding amino acid sequence of human FGF23
  • Figure 6 Exemplary coding sequence and corresponding amino acid sequence of human adiponectin
  • the examples show:
  • Example I Methods for evaluation of FGF23 as a parameter for CKD
  • Exclusion criteria were treatment with immunosuppressive agents, fish oil or erythropoietin, serum creatinine above 6 mg/dL, diabetes mellitus of any type, malignancy, liver, thyroid or infectious disease, nephrotic syndrome (defined as proteinuria >3.5 g/1.73 m 2 /day), organ transplantation, allergy to ionic contrast media and pregnancy.
  • kidney disease The primary cause of kidney disease was glomerulonephritis in 97 (biopsy-confirmed in 90) patients, adult polycystic kidney disease in 37 patients, interstitial nephritis in 24 patients, other types of kidney disease in 43 patients and unknown in 26 patients.
  • the inter-assay coefficients of variability for the latter are 6.5% at 40 rU/mL, and 7.5% at 175 rU/mL respectively, and the lower detection limit is 3.0 rU/mL.
  • Measurements of routine chemistry including hsCRP were performed with routine laboratory tests.
  • GFR was assessed in all patients using the iohexol clearance technique as described in Bostom, (2002) J. Am. Soc. Nephrol. 13, 2140- 2144.
  • Example II Stages of CKD and calcium-phosphate metabolism and corresponding progression of CKD
  • Example III FGF23 as a novel risk marker for the progression of CKD
  • FGF23 was identified as a novel risk marker for the progression of CKD.
  • FGF23 was the only independent predictor of progression among several parameters of calcium-phosphate metabolism assessed.
  • FGF23 is a recently identified "phosphatonin” which is thought to be implicated in the systemic balance of phosphate maintained by the interaction of intestine, bone and the kidneys (Berndt, (2005) loc. cit.; Weber, (2003), loc. cit.; Fugakawa, (2005) Nephrol. Dial. Transplant 20, 1295-1298).
  • phosphatonin a recently identified "phosphatonin” which is thought to be implicated in the systemic balance of phosphate maintained by the interaction of intestine, bone and the kidneys.
  • FGF23 is an excellent indicator of the complex changes in calcium-phosphate metabolism induced by CKD, and probably also a very suitable surrogate parameter of the sequelae of these metabolic alterations.
  • the latter comprises mainly calcification of intimal plaques and of the media of central arteries (M ⁇ nckeberg sclerosis) (Schwarz, (2000) Nephrol. Dial. Transplant. 15, 218-223).
  • M ⁇ nckeberg sclerosis mainly calcification of intimal plaques and of the media of central arteries (M ⁇ nckeberg sclerosis) (Schwarz, (2000) Nephrol. Dial. Transplant. 15, 218-223).
  • adiponectin plasma concentrations were measured with an ELISA (R&D Systems, Minneapolis, MN). Glomerular filtration rate (GFR) was assessed in all patients using the iothalamate clearance technique as described in detail elsewhere (Bostom, (2002), loc. cit.). Criteria for clinical diagnosis of metabolic syndrome were defined according to the scientific statement from the American Heart Association (AHA) and the National Heart, Lung, and Blood Institute (NHLBI) (Grundy, (2005) Circulation 112, 2735-2752). The insulin sensitivity in the patients was also quantified, using the Homeostasis Model Assessment of Insulin Resistance (HOMA-IR): plasma insulin (mU/L) x plasma glucose (mg/dL) - 405.
  • HOMA-IR Homeostasis Model Assessment of Insulin Resistance
  • Example V Adiponectin as marker of CKD progression in men
  • adiponectin concentrations were not a significant predictor in either model, whereas in men, adiponectin was a significant predictor of disease progression in all models (p ⁇ 0.0001 ) (part 2 of Table 6).
  • Adiponectin levels were still significantly associated with disease progression in men even when adjusted for asymmetric dimethylarginine or apolipoprotein A-IV, which was recently shown to be significant predictors of progression (Boes, (2006, loc. cit.; Fliser, (2005) J. Am. Soc. Nephrol. 16, 2456-2461). Metabolic syndrome, insulin, and HOMA-IR were not associated with disease progression.
  • adiponectin increases energy expenditure and induces weight loss through a direct effect on the brain (Fruebis, (2001) Proc. Natl. Acad. Sci. USA 98, 2005-2010; Qi 1 (2004) Nat. Med. 10, 524-529). It has been proposed that in the context of increased energy expenditure high plasma adiponectin levels might not be beneficial in CHF. And the same is potentially true in renal patients.
  • CHF and CKD patients may have much in common and many traditional risk factors such as hypercholestrolemia, hypertension or high BMI may provide beneficial outcomes, a well known constellation which is called "reverse epidemiology" (Kalantar-Zadeh, (2006) Semin. Nephrol. 26, 118-133). Patients with CKD often develop CHF (Al Ahmad, (2001) J. Am. Coll. Cardiol. 38, 955-962; McClellan, (2002) J. Am. Soc. Nephrol.
  • N-terminal pro brain natriuretic peptide (NT-proBNP) levels with decreasing kidney function, found by us and others recently (Luchner, (2005) Hypertension 46, 1-6; DeFilippi, (2005) Am. J. Kidney Dis. 46, 35-44) (Spanaus et al, unpublished results).
  • NT-proBNP N-terminal pro brain natriuretic peptide
  • adiponectin resistance (Kadowaki, (2005) Endocr. Rev. 26, 439-451 ; Furuhashi, (2004) Diabetes Care 27, 2217-2221) caused by dysfunction or downregulation of adiponectin receptors with consecutive counterregulatory increased adiponectin secretion.
  • Such adiponectin resistance might be analogous to the finding of virtually absent uptake of adiponectin across the coronary bed found in diabetic compared to non-diabetic patients (Furuhashi, (2004), loc. cit.).
  • Adiponectin levels are much less predictive for CKD progression in women although women have significantly higher adiponectin levels compared to men.
  • An explanation for this finding might again be the presence of adiponectin resistance, the latter being more pronounced in men than in women.
  • This assumption is in line with the observation that in our cohort of women a metabolic syndrome was less frequent and the number of components of the metabolic syndrome was lower compared to men. This finding is different from the general population in which the metabolic syndrome tends to be more frequent in women (Reynolds, (2005) Am. J. Med. Sci 330, 273- 279). Without being bound by theory, it is speculated that the ligand-receptor interaction might be less disturbed in women compared to men.
  • adiponectin was identified as a novel predictor for CKD progression in men but not in women. This observation is also of relevance for other conditions of progressive vascular sclerosis.
  • Table 1 Baseline clinical and laboratory data of 227 patients stratified according to glomerular filtration rate.
  • Serum creatinine (mg/dL) 1.14 ⁇ 0.22 1.54 ⁇ 0.45 2.31 ⁇ 0.79 3.63 ⁇ 1.27 ⁇ 0.0001
  • Proteinuria (g/24h/1.73m 2 ) 0.60 ⁇ 0.66 1.10 ⁇ 1.10 1.08 ⁇ 0.94 1.03 ⁇ 0.81 0.004
  • Serum albumin (g/dL) 4.70 ⁇ 0.38 4.46 ⁇ 0.50 4.55 ⁇ 0.38 4.53 ⁇ 0.34 0.01
  • Table 2 Clinical and laboratory data of 177 patients with completed follow-up with further stratification to those with and without progression during the follow-up period.
  • Fibroblast growth factor 23 (rU/mL) 92 ⁇ 113 351 ⁇ 394 d
  • GFR glomerular filtration rate
  • FGF23 fibroblast growth factor 23
  • Ca x P product calcium x phosphate product.
  • Table 4 The association of variables of the calcium-phosphate metabolism with progression of kidney disease during the observation period using multiple Cox Proportional Hazards regression models. Fibroblast growth factor 23 (FGF23) was not included in these models.
  • Table 5 Baseline clinical and laboratory data of 177 patients who completed follow-up with further stratification into those without and with progression of kidney disease during the follow-up period
  • C-reactive protein 0.28 ⁇ 0.31 0.28 ⁇ 0.32 0.29 ⁇ 0.31
  • Proteinuria (1g/24h/1.73m 2 ) 1.30 (1.02-1.65) 0.032 1.29 (0.98-1.70) 0.065
  • Insulin (1 mU/L) 0.98 (0.96-1.02) 0.31 0.98 (0.86-1.13) 0.81

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Abstract

La présente invention concerne une méthode destinée à la détection et à la prévision de l'évolution de la néphropathie chronique chez un sujet susceptible de souffrir de néphropathie chronique. Cette méthode comprend une étape qui consiste à déterminer les niveaux d'expression d'au moins un marqueur sélectionné parmi (a) le FGF-23 et (b) l'adiponectine dans un prélèvement biologique. La présente invention concerne également une utilisation d'une molécule de détection spécifique pour le FGF-23 ou l'utilisation d'une molécule de détection spécifique pour l'adiponectine pour la préparation d'une composition diagnostique destinée à la détection de la néphropathie chronique ou à la prévision de l'évolution de maladies rénales chroniques chez un sujet susceptible de souffrir de cette maladie. La présente invention concerne en particulier l'utilisation du FGF-23 et/ou de l'adiponectine comme marqueur in vitro de la présence, de l'absence ou de l'évolution d'une néphropathie chronique, ainsi que des trousses comprenant une molécule de détection spécifique pour le FGF-23 ou une molécule de détection spécifique pour l'adiponectine, destinées à être utilisées dans la méthode de la présente invention.
PCT/EP2008/000420 2007-01-22 2008-01-21 Nouveaux marqueurs pour la néphropathie chronique WO2008089936A1 (fr)

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WO2010052334A1 (fr) * 2008-11-10 2010-05-14 F. Hoffmann-La Roche Ag Pertinence de la fonction intestinale des adipocytes dans le diabète de type 1
EP3244213A1 (fr) * 2009-02-06 2017-11-15 Astute Medical, Inc. Procédés et compositions pour le diagnostic et le pronostic de lésion rénale et insuffisance rénale
WO2010107667A2 (fr) * 2009-03-18 2010-09-23 Mayo Foundation For Medical Education And Research Evaluation de fonction rénale
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WO2012012704A2 (fr) 2010-07-23 2012-01-26 President And Fellows Of Harvard College Procédés de détection de maladies ou d'états associés au rein
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